1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors

Puwen Zhang; Eugene A Terefenko; Jenifer Bray; Darlene Deecher; Andrew Fensome; Jim Harrison; Callain Kim; Elizabeth Koury; Lilly Mark; Casey C McComas; Cheryl A Mugford; Eugene J Trybulski; An T Vu; Garth T Whiteside; Paige E Mahaney

doi:10.1021/jm900888c

1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors

J Med Chem. 2009 Sep 24;52(18):5703-11. doi: 10.1021/jm900888c.

Authors

Puwen Zhang¹, Eugene A Terefenko, Jenifer Bray, Darlene Deecher, Andrew Fensome, Jim Harrison, Callain Kim, Elizabeth Koury, Lilly Mark, Casey C McComas, Cheryl A Mugford, Eugene J Trybulski, An T Vu, Garth T Whiteside, Paige E Mahaney

Affiliation

¹ Chemical Sciences, Wyeth Research, S-2250B, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Zhangp@wyeth.com

PMID: 19722525
DOI: 10.1021/jm900888c

Abstract

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.

MeSH terms

Administration, Oral
Animals
Behavior, Animal / drug effects
Benzimidazoles / administration & dosage
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
Biological Transport / drug effects
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
Female
Humans
Hyperalgesia / physiopathology
Male
Neurotransmitter Uptake Inhibitors / administration & dosage
Neurotransmitter Uptake Inhibitors / chemistry*
Neurotransmitter Uptake Inhibitors / pharmacokinetics
Neurotransmitter Uptake Inhibitors / pharmacology*
Norepinephrine / metabolism*
Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
Propanolamines / chemistry
Rats
Rats, Sprague-Dawley
Serotonin Plasma Membrane Transport Proteins / metabolism
Spinal Nerves / drug effects
Spinal Nerves / physiology
Structure-Activity Relationship
Substrate Specificity

Substances

Benzimidazoles
Dopamine Plasma Membrane Transport Proteins
Neurotransmitter Uptake Inhibitors
Norepinephrine Plasma Membrane Transport Proteins
Propanolamines
Serotonin Plasma Membrane Transport Proteins
benzimidazol-2-one
Norepinephrine